Among treatments for clinical infertility, assisted reproductive technologies (ART) have the highest live birth rate per treatment. Voorhis, The New England Journal of Medicine 356:379-386 (2007). ART has contributed to the conception of 1% of live births in the United States per year and more than 1 million babies worldwide since its inception. Bonduelle et al., Human Reproduction (Oxford, England) 20:413-419 (2005); Sunderam et al., MMWR Surveill Summ 58:1-25 (2009). There are, however, many medical, socio-economical, and ethical challenges associated with the implementation of ART that remain unresolved. For example, the decision of couples to pursue ART or to repeat ART treatment after a failed attempt is often a difficult decision due to the physical, emotional, and financial costs of treatment. Further, ART procedures provide no certainty regarding the outcome of a live birth event, a multiple birth event, or the associated maternal/fetal/neonatal complications associated with the live birth or multiple birth event.
With regard to multiple gestations, in the United States in 2006, ART contributed disproportionately to 18% of multiple gestations with 17% of the gestations being twins and 38% of the gestations being triplets or higher-order multiples; consequently 49% of ART infants were born from multiple gestations, compared to 3% in the general U.S. population. Sunderam et al., supra. Further, in 2006 in the U.S., 41% of ART infants were born preterm compared to the national preterm rate of 13%; therefore, ART contributed to 4% of all preterm births in the U.S. Sunderam et al., supra; Osterman et al., National Vital Stat Rep 57:1-104 (2009). Many preterm births in ART may be directly attributable to the high incidence of multiple gestations in ART. To illustrate, in 2006, 65% of ART twins and 13% of ART singletons were born preterm, compared to 11% in the general U.S. population. Similarly, 57% of ART twins, and 9% of ART singletons were born with low birth weight, compared to 6% in the general U.S. population. Sunderam et al. supra. While these national statistics potentially underestimate the differences since the general population might have comprised births conceived by ART and non-ART ovarian stimulation, the national statistics indicate that the ART population is at high risk for preterm birth and multiple gestations.
Many studies have reported increased risks of adverse obstetrical and neonatal outcomes in twin births resulting from ART. An exemplary study based on ART births retrieved from the Danish IVF/ICSI (in vitro fertilization/intracytoplasmic sperm injection) registry and its National Medical Birth Registry between 1995-2000 reported neonatal outcomes for 8602 births of which 40% were twins and 60% were singletons Pinborg et al., Acta Obstetricia et Gynecologica Scandinavica 83:1071-1078 (2004). Compared to ART singletons, ART twins had a 10-fold increased risk of preterm delivery prior to 37 gestational weeks and 7.4-fold increased risk of preterm delivery prior to 32 gestational weeks. In the U.K., ART twins had an 11-fold increased risk of low birth weight (<2500 g) and a 5-fold increased risk of very low birth weight (<1500 g). Sutcliffe et al., Lancet 370:351-359 (2007). In addition, the incidence of stillbirths, cesarean section, and NICU admission were also increased for ART gestations. Similar findings have been reported by many ART centers. Id.
With regard to multiple birth events, presently, there are no validated prediction tools to assess the risks of multiple births in cases that have two or more embryos transferred. Efforts to minimize the risks of multiple gestations are challenged by the current lack of an optimal method for selecting patients for elective single embryo transfer (eSET), which is the procedure by which a single embryo is transferred to the uterus of an abstaining patient to completely eliminate the risk of having dizygotic twins, which is the predominant cause of multiple gestations, and hence preterm birth attributed to multiple gestations in ART. While eSET has been reported to decrease multiple gestation rates without compromising live birth rates by some, others have found that the implementation of eSET compromised per cycle or cumulative live birth rates and failed to reduce multiple gestation rates. Kalu et al., BJOG 115:1143-1150 (2008); Khalaf et al., BJOG 115:385-390 (2008); Styer et al., Fertility and Sterility 89:1702-1708 (2008).
Fertility physicians typically discuss the risk of multiple births with their patients prior to starting IVF or other fertility treatments, and then again just prior to embryo transfer (ET), which is the act of transferring embryos back to the womb. The discussion between the physician and the patient regarding the number of embryos to transfer is typically based on a discussion of the probabilities of multiple births and pregnancies as a function of the age of the female, the number of embryos transferred, and the embryo quality. When deciding whether to pursue multiple embryos or eSET, the physician typically adheres to the guidelines set forth by the American Society for Reproductive Medicine (ASRM). The ASRM has established guidelines for eSET patient selection that are largely based on the women's age and the total number of embryos. Fertility and Sterility 90:S163-164 (2008). Perhaps realizing the limitations of those guidelines, ASRM also recommends that each ART center use its own data to guide the number of embryos for transfer.
Following the guidelines established by the ASRM or Center for Disease Control (CDC), physicians and their patients are currently attempting to decrease the incidence of multiple births resulting from IVF by transferring fewer embryos, if not a single embryo. There is a general perception, however, that eSET decreases the probability of live births, but it is not known if there are specific subsets of patients who are at higher risks for multiple births. For example, it is possible that certain patients may be at very low risk for multiple births, but their probability of having a live birth may be significantly compromised if they were to pursue eSET instead of having two embryos transferred. In contrast, other patients may be at relatively high risk for multiple births, such that pursuing eSET may dramatically decrease their families' health risks. Presently, there is no way to determine if a particular female patient would benefit more from eSET than another patient.
The foregoing discussion demonstrates that multiple births are a significant health and socioeconomic problem for patients who are undergoing infertility treatment and that the current state of the art does not provide an effective way to be able to avoid multiple births and/or assure the success of eSET.